Naphthyl piperazines useful as 5-HT1A receptor ligands

ABSTRACT

Compounds of formula I: ##STR1## in which: N=1-4, 
     R represents hydrogen, halogen, alkyl, hydroxyl or alkoxy, R 1  represents a radical -NHCOR2 (A 1 ); (in which R 2  represents alkyl, cycloalkyl, phenyl, optionally substituted-, -O-alkyl, 3-pyridyl, 2-pyrrolyl, quinolyl, 1-isoquinolyl, 2-thienyl or 3-indolyl); a radical of --NHSO2R3 (A 2 ) (in which R 3  represents alkyl, cycloalkyl or phenyl optionally substituted); a radical --NHCONHR4 (A 3 ) (in which R 4  represents alkyl or phenyl-optionally substituted); a phthalimido radical (A 4 ); an o-sulfobenzoic imido radical (A 5 ); a di(benzoyl)amino radical (A 6 ) optionally substituted; a radical of formula A 7  : ##STR2##  (in which R 5  represents carbamoyl, cyano, carboxy or alkoxycarbonyl); or a radical of formula A 8  : ##STR3##  their stereoisomers and their addition salts with a pharmaceutically-acceptable inorganic or organic acid, are disclosed to be useful as 5-HT 1A  receptor ligands and accordingly as the active principle in medicinal products containing the same.

The present invention is a division of our prior-filed copendingapplication Ser. No. 07/629,824, filed Dec. 19, 1990, now U.S. Pat. No.5,126,346.

The present invention relates to new (1-naphthyl)piperazine compounds.

Some (1-naphthyl)-4-alkylpiperazine compounds having neuroleptic orantipsychotic properties are described in U.S. Pat. No. 4,831,031 and inpatent applications EP 281,309 and EP 279,598.1-[3-(3,4,5-Trimethoxyphenoxy)-2-hydroxypropyl]-4-arylpiperazinecompounds having antiaggressive activity are described in U.S. Pat. No.4,335,126. Arylpiperazine compounds having antagonist activity at the5-HT_(1A) receptor level are described in J. Med. Chem., (1989), 32, p.1921-1926 and Drug Dev. Res., (1989), 16, p. 335-343. It is also knownthat (1-naphthyl)piperazine is a ligand of serotonin receptors (Journalof Receptor Research, (1988), (1-4), p. 59-81).

The compounds of the invention are distinguished from the other(1-naphthyl)piperazine compounds described in the literature by theirnovel structures and by their pharmacological properties.

At cardiovascular level, the compounds of the invention decreasearterial blood pressure and heart rate. This action results from centralinhibition of sympathetic tonus and is linked with their 5-HT_(1A)agonist properties. At central nervous system level, the compounds ofthe invention have demonstrated 5-HT_(1A) agonist or antagonistproperties. They can hence be useful in the treatment of migraine,depression, anxiety, schizophrenia, stress and pain.

The subject of the present invention is, more especially, the(1-naphthyl)piperazine compounds of general formula (I): ##STR4## inwhich n represents an integer from 1 to 4,

R represents a hydrogen atom, a halogen atom, an alkyl radical having 1to 6 carbon atoms, a hydroxyl radical or an alkoxy radical having 1 to 6carbon atoms,

R represents a radical of formula A₁ : ##STR5## (in which R₂ representsan alkyl radical having 1 to 6 carbon atoms, a cycloalkyl radical having3 to 7 carbon atoms, a phenyl radical optionally substituted with one ormore halogen atoms, with one or more alkyl radicals having 1 to 6 carbonatoms or with one or more alkoxy radicals having 1 to 6 carbon atoms--an--O--alkyl radical having 1 to 6 carbon atoms, a 3-pyridyl radical, a2-pyrrolyl radical, a quinolyl radical, a 1-isoquinolyl radical, a2-thienyl radical or a 3-indolyl radical),

a radical of formula A₂ : ##STR6## (in which R₃ represents an alkylradical having 1 to 6 carbon atoms, a cycloalkyl radical having 3 to 7carbon atoms or a phenyl radical--optionally substituted with one ormore halogen atoms, with one or more alkyl radicals having 1 to 6 carbonatoms or with one or more alkoxy radicals having 1 to 6 carbon atoms),

a radical of formula A₃ :

    --NHCONHR.sub.4                                            (A.sub.3)

(in which R₄ represents an alkyl radical having 1 to 6 carbon atoms or aphenyl radical optionally substituted with one or more halogen atoms orwith one or more alkyl or alkoxy radicals having 1 to 6 carbon atoms),

a phthalimide radical of formula A₄ : ##STR7## (with the proviso,however, that when n represents, 4, R does not represent a hydrogenatom),

an o-sulfobenzoic imido radical of formula A₅ : ##STR8## or a radical offormula A₆ : ##STR9## (in which formulae X, Y and Z, which nay beidentical or different, each represent a hydrogen atom, a halogen atom,an alkyl radical having 1 to 6 carbon atoms or an alkoxy radical having1 to 6 carbon atoms), or

a radical of formula A₇ : ##STR10## (in which R₅ represents a carbamoylradical, a cyano radical, a carboxy radical or an alkoxycarbonyl radicalhaving 1 to 6 carbon atoms), or

a radical of formula A₈ : ##STR11## their stereoisomers and theiraddition salts with a pharmaceutically acceptable inorganic or organicacid.

The subject of the present invention is also a process for preparingcompounds of general formula I, wherein there is used as a startingmaterial:

a/ either:

a compound of formula II: ##STR12## in which R has the same meaning asfor the formula I, which is condensed: either with a nitrile of formulaIII:

    Hal(CH.sub.2).sub.n-1 CN                                   (III)

in which Hal represents a halogen atom and n has the same meaning as forthe formula I, in an organic solvent, at room temperature, in thepresence of an alkali metal salt, to obtain the compounds of formula IV:##STR13## in which R and n have the same meaning as for the formula I,which is converted by means of lithium aluminum hydride or anotherequivalent chemical reagent to a compound of formula V: ##STR14## inwhich R and n have the same meaning as for the formula I, which isreacted

either with an equimolar quantity of a compound of formula VI_(A) orVI_(B) :

    ClCOR.sub.2                                                (VI.sub.A)

    ClSO.sub.2 R.sub.3                                         (VI.sub.B)

in which R₂ and R₃ have the same meanings as for the formula I, toobtain, respectively, the compounds of formula I in which R₁ representsa radical Of formula A₁ and the compounds of formula I in which R₁represents a radical of formula A₂, the compounds of formula I in whichR₂ represents an --O-alkyl radical being reacted, if so desired, with acompound of formula VII :

    R.sub.4 NH.sub.2                                           (VII)

in which R₄ has the same meaning as for the formula I, to form thecompounds of formula I in which R₁ represents a radical of formula A₃,

or

with an excess of a compound of formula VIII: ##STR15## in which X, Yand Z have the same meaning as for the formula I, to form a compound offormula I in which R₁ represents a radical of formula A₆,

or

with a compound of formula IX_(A) or IX_(B) : ##STR16## in which Hal hasthe same meaning as for the formula III and X, Y and Z have the samemeaning as for the formula I, to form, respectively, the compounds offormula I in which R₁ is a radical of formula A₄ or a radical of formulaA₅,

or

with an alcohol of formula X:

    Hal(CH.sub.2).sub.n OH                                     (X)

in which n has the same meaning as for the formula I and the meaning ofHal remains identical to that given for the formula III, to form thecompounds of formula XI: ##STR17## in which R and n have the samemeaning as for the formula I, which is subjected to the action ofthionyl chloride or of another equivalent chemical reagent to form thecompounds of formula XII: ##STR18## in which R and n have the samemeaning as for the formula I, which is condensed

either

with ethyl acetoacetate to form a compound of formula XIII: ##STR19## inwhich n and R have the same meaning as for the formula I, which iscondensed with a 4-aminoimidazole derivative of formula XIV: ##STR20##in which R₅ has the same meaning as for the formula I, to form thecompounds of formula I in which R₁ represents a radical of formula A₇,

or

with a compound of formula XV ##STR21## to form the compounds of formulaI in which R₁ represents a radical of formula A₈,

a compound of formula XVI: ##STR22## in which R has the same meaning asin the formula I, which is condensed with N-benzyliminodiacetic acid offormula XVII, refluxed beforehand with carbonyldiimidazole in ananhydrous solvent such as tetrahydrofuran according to the techniquedescribed by C. G. Kruse and J. J. Trost (Recueil des travaux chimiquesdes Pays-Bas, 107, 303-309, 1988) ##STR23## to lead to a2,6-piperazinedione of formula XVIII: ##STR24## in which R has the samemeaning as in the formula I, on which a catalytic hydrogenation iscarried out in the presence of palladinized charcoal as a catalyst, tolead to a 2,6-piperazinedione of formula XIX: ##STR25## in which R hasthe same meaning as in the formula which is condensed either

with a nitrile of formula III:

    Hal--(CH.sub.2).sub.n-1 --CN                               (III)

in which Hal and n have the same meaning as above, to lead to a2,6-piperazinedione of formula XX: ##STR26## in which R and n have thesame meaning as in the formula I, which is reduced in the presence ofthe borane/dimethyl sulfide complex according to the technique describedby H. C. Brown et al. (J. Org. Chem., 47, 3153-3163, 1982) to lead to apiperazine of formula V: ##STR27## in which R and n have the samemeaning as in the formula I, which is reacted

either

with an equimolar quantity of a compound of formula VI_(A) or VI_(B) :

    ClCOR.sub.2                                                (VI.sub.A)

    ClSO.sub.2 R.sub.3                                         (VI.sub.B)

in which R₂ and R₃ have the same meanings as for the formula I, toobtain, respectively, the compounds of formula I in which R₁ representsa radical of formula A₁ and the compounds of formula I in which R₁represents a radical of formula A₂, the compounds of formula I in whichR₂ represents an --O--alkyl radical being reacted, if so desired, with acompound of formula VII :

    R.sub.4 NH.sub.2                                           (VII)

in which R₄ has the same meaning as for the formula I, to form thecompounds of formula I in which R₁ represents a radical of formula A₃,

or

with an excess of a compound of formula VIII: ##STR28## in which X, Yand Z have the same meaning as for the formula I, to form a compound offormula I in which R₁ represents a radical of formula A₆,

or

with an alcohol of formula X:

    Hal(CH.sub.2).sub.n OH                                     (X)

in which Hal and n have the same meaning as above, to lead to a2,6-piperazinedione of formula XXI: ##STR29## in which R and n have thesame meaning as in the formula I, which is subjected to the action ofthionyl chloride or of another equivalent chemical reagent, to lead to a2,6-piperazinedione of formula XXII: ##STR30## in which R and n have thesame meaning as in the formula I, which is reduced in the presence ofthe borane/dimethyl sulfide complex according to the technique describedby H. C Brown et al. (J. Org. Chem., 47, 3153-3163, 1982) to lead to apiperazine of formula XII: ##STR31## in which R and n have the samemeaning as in the formula I, which is condensed

either

with a compound of formula XXIII_(A), XXIII_(B) or XV ##STR32## to lead,respectively, to the compounds of formula I in which R₁ is a radical A₄,A₅ or A₈,

or

with ethyl acetoacetate to form a compound of formula XIII ##STR33## inwhich n and R have the same meaning as for the formula I, which iscondensed with a 4-aminoimidazole derivative of formula XIV: ##STR34##in which R₅ has the same meaning as for the formula I, to form thecompounds of formula I in which R₁ represents a radical of formula A₇,

which compounds of formula I are then, if so desired, salified with apharmaceutically acceptable organic or inorganic acid to form thecorresponding addition salts.

The compounds of formula II are obtained according to the processdescribed in Collection Czechoslov Chem. Commun., (1975), 40, p. 1612.The preparation of 1-(7-methoxy-1-naphthyl)piperazine is also known (J.Med. Chem., (1989), 32, No. 8, p. 1921).

The reaction of the compound of formula II with the compound of formulaIII is performed at room temperature, and preferably in the presence ofpotassium carbonate or sodium carbonate. The compounds of formula IV areconverted to a compound of formula V at room temperature in an organicsolvent, preferably tetrahydrofuran. The same working conditions arealso used for the reaction of the compounds of formula V with thecompounds of formula VI_(A) or VI_(B). The reaction is performed in thepresence of triethylamine, and likewise the reaction of the compounds offormula V with the compounds of formula VIII.

The reaction of the compounds of formula VII with the compounds offormula I in which R₂ represents an --O--alkyl radical is described inJ. Chem. Soc., (1949), p. 1732-1738.

Among the pharmaceutically acceptable acids for the preparation ofaddition salts with the compounds of general formula I, hydrochloric,phosphoric, fumaric, citric, oxalic, sulfuric, ascorbic, tartaric,maleic, mandelic and methanesulfonic acids, and the like, may bementioned.

The compounds of the present invention possess highly advantageouspharmacological properties. At cardiovascular level, the compounds ofthe invention decrease arterial blood pressure and heart rate in ratsand in dogs. This action results from a central inhibition ofsympathetic tonus. In effect, pharmacological tests have shown that thefall in pressure caused by i.v. administration of the compounds of theinvention in dogs is accompanied by a strong decrease in the electricalactivity of the renal sympathetic nerve.

This central decrease in sympathetic tonus results from an activation ofthe central 5-HT_(1A) receptors at the level of the retrofacial nucleus(Eur. Journal of Pharm., (1989) 160, p. 385-294). The pharmacologicaltests also showed that the compounds of the invention are approximately3 times as active as flesinoxan, a reference compound havingantihypertensive properties due to its 5-HT_(1A) receptor agonistactivity (European Journal of Pharmacology, (1988), 149, p. 213-223).Moreover, the compounds of the invention have a beneficial activity atrenal level (T.I.P.S., (1989), 10, p. 469-471).

Binding tests confirmed that the compounds of the invention also behaveas very potent ligands of 5-HT_(1A) receptors, with an agonist orantagonist activity at central nervous system level.

The compounds of the invention hence find their application in thetreatment of stress (Neuropharmac., ( (1989), Vol. 25, No. 5, p.471-476), migraine (T.I.P.S., (1989), Vol. 10, pp. 200-204), anxiety,depression, schizophrenia and pain (Pharmacology and Toxicology, (1989),64, p. 3-5), (Drugs of the Future, (1988), 13, No. 5, p. 429-437), (J.Neural. Transm., (1988), 74, p. 195-198).

The compounds active at 5-HT_(1A) receptor level can also modify feedingand sexual behavior (Jour. of Receptor Research, (1988), 8, p. 59-81).

The invention also encompasses pharmaceutical compositions containing asactive principle at least one compound of general formula I, or one ofits salts with a pharmaceutically compatible inorganic or organic acid,in combination with one or more inert and suitable excipients.

The pharmaceutical compositions thereby obtained are advantageouslypresented in various forms such as, for example, tablets, dragees, hardgelatin capsules, suppositories, injectable solutions or solutions to betaken by mouth.

The dosage can vary widely in accordance with the patient's age andweight, the nature and severity of the condition and also theadministration route. Generally speaking, the single doses will rangebetween 0.05 and 10 mg, and the daily dosage usable in human therapybetween 0.05 and 20 mg. The preferred administration route is the oralor parenteral route.

The examples which follow, given without implied limitation, illustratethe invention.

The melting points were measured according to the micro-Koflertechnique.

The proton nuclear magnetic resonance (¹ H NMR) or ¹³ C carbon nuclearmagnetic resonance (¹³ C NMR) spectra of the compounds of generalformula I were recorded, depending on the case, at 200 and 400 MHz, andare shown in Table I.

EXAMPLE 1

1-(6-Methoxy-1-naphthyl)-4-[2-(4-fluorobenzoylamino)ethyl]piperazinehydrochloride

Stage A

1-Amino-6-methoxynaphthalene hydrochloride

19.5 g of 1-amino-6-hydroxynaphthalene are added in small quantities toa solution of sodium methanolate (2.82 g of sodium metal in 80 ml ofmethanol). The medium is stirred for one hour at room temperature andthe solvent is then evaporated off under vacuum. The residue obtained isdissolved in 700 ml of acetone, and 9.27 g of dimethyl sulfate are addeddropwise while a temperature below 60° C. is maintained. When theaddition is complete, the medium is stirred for 12 hours at roomtemperature. The precipitate formed is filtered off, the filtrate istreated with active charcoal and the solvent is evaporated off undervacuum. The oil thereby obtained is purified by chromatography on 1 kgof 70-230 mesh silica using dichloromethane as eluent.

Yield: 55%.

Proton nuclear magnetic resonance spectrum (Solvent CDCl₃): 3.9 ppm, s,3H; 4.1 ppm, 1H exchangeable; 6.6 ppm, dd, 1H; 7.0-7.3 ppm, m, 3H; 7.05ppm, m, 1H; 7.65 ppm, d, 1H.

Stage B

1-(6-Methoxy-1-naphthyl)piperazine hydrochloride

A mixture of 4.1 g of the compound obtained in the preceding stage and4.7 g of N,N-bis(chloroethyl)-amine hydrochloride in 150 ml ofchlorobenzene is brought to reflux for 24 hours. The precipitate isfiltered off, washed with ether and recrystallized in ethanol to yieldthe expected product.

Yield: 70%.

Proton nuclear magnetic resonance spectrum (Solvent DMSO-d₆): 3.1-3.5ppm, m, 8H; 3.9 ppm, s, 3H; 6.70 ppm, d, 1H; 7.15 ppm, m, 1H; 7.50 ppm,d, 1H; 7.8-7.5 ppm, m, 3H.

Stage C

[4-(6-Methoxy-1-naphthyl)piperazino]acetonitrile

A mixture of 5.8 g of the compound obtained in Stage B, 2.8 g of2-bromoacetonitrile and 6.4 g of potassium carbonate in 250 ml ofacetone is stirred at room temperature until the starting piperazine hascompletely disappeared, this being observed by TLC (eluent:dichloromethane/acetone 95:5 V/V). The medium is then filtered and thesolvent evaporated off under vacuum. The product crystallizes in aminimum amount of ether.

Yield: 70%. Elemental analysis:

    ______________________________________                                        Elemental analysis:                                                                    C %         H %    N %                                               ______________________________________                                        Calculated:                                                                              72.57         6.81   14.93                                         Found:     72.44         7.01   14.67                                         ______________________________________                                    

Stage D

1-(6-Methoxy-1-naphthyl)-4-(2-aminoethyl)-piperazine

A solution containing 4.2 g of the compound obtained in Stage C, in 25ml of tetrahydrofuran is added dropwise at room temperature to asuspension, stirred under a nitrogen atmosphere, of 1.1 g of lithiumaluminum hydride in 25 ml of tetrahydrofuran. Stirring is main-tainedfor 20 minutes after the addition is complete, and the reaction mediumis then hydrolyzed with the requisite quantity of water saturated withammonium chloride. The precipitate formed is filtered off and washedwith tetrahydrofuran, and the filtrates are concentrated under vacuum toyield an oil.

Yield: 74%.

Proton nuclear magnetic resonance spectrum (Solvent CDCl₃): 3.1-3.6 ppm,4H; 3.1-4.0 ppm, 4+4H; 3.85 ppm, s, 3H; 7.0 ppm, d, 1H; 7.15 ppm, dd,1H; 7.2-7.4 ppm, t+d, 1+1H; 7.6 ppm, d, 1H; 7.95 ppm, d, 1H.

Stage E

1.8 g of 4-fluorobenzoyl chloride in 50 ml of tetrahydrofuran are addedto a solution, stirred at room temperature, of 3 g of the compoundobtained in Stage D and 1.7 g of triethylamine in 20 ml oftetrahydrofuran. After contact for two hours, the reaction medium isfiltered. The filtrate is concentrated under vacuum and the productobtained is crystallized in ether.

Yield: 76%.

Melting point: 180° C.

3 1 g of the base are dissolved in 300 ml of ethanol, and a requisitequantity of 6N methanolic hydrogen chloride is added dropwise. Thehydrochloride precipitates.

Melting point: ≧260° C.

EXAMPLE 2

1-(6-Hydroxy-1-naphthyl)-4-[2-(4-fluorobenzoylamino)ethyl]piperazinehydrochloride

A solution of 0.85 g of the compound of Example 1, in base form, in 40ml of dichloromethane is cooled to -20° C. under a nitrogen atmosphere.10 ml of a molar solution of boron tribromide in dichloromethane arethen added dropwise while the temperature is maintained at -20°-20° C.When the addition is complete, the medium is slowly heated to roomtemperature and stirred at this temperature for one hour before beinghydrolyzed with 2 ml of ammonia solution. The organic phase, separatedafter settling has taken place, is dried over anhydrous magnesiumsulfate and the solvent evaporated off under vacuum; the residue isdissolved in 20 ml of ethanol and the hydrochloride is precipitated byadding 0.4 ml of 6N ethanolic hydrogen chloride.

Yield: 72.

Melting point: 216° C,

EXAMPLE 3

1-(7-Methoxy-1-naphthyl)-4-[2-(4-fluorobenzoylamino)ethyl]piperazinehydrochloride

Stage A

[4-(7-Methoxy-1-naphthyl)piperazino]acetonitrile

This compound is obtained from (7-methoxy-1-naphthyl)piperazineaccording to the process described in Example 1, Stage C.

Yield: 74%.

Proton nuclear magnetic resonance spectrum (Solvent CDCl₃): 2.9 ppm, t,4H; 3.2 ppm, m, 4H; 3.65 ppm, s, 2H; 3.95 ppm, s, 3H; 7.0-7.35 ppm, m,3H; 7.5 ppm, m, 2H; 7.7 ppm, d, 1H.

Stage B

1-(7-Methoxy-1-naphthyl)-4-(2-aminoethyl)-piperazine

This compound is obtained according to the method described in Example1, Stage D, from [4-(7-methoxy-1-naphthyl)piperazino]acetonitrile.

Yield: 97%.

Proton nuclear magnetic resonance spectrum (Solvent DMSO-d₆): 3.1-3.55ppm, m, 10H; 3.75 ppm, d, 2H; 3.95 ppm, s, 3H; 7.0-7.4 ppm, m, 3H; 7.4ppm, d, 1H; 7.6 ppm, d, 1H; 7.85 ppm, d, 1H; 8.6 ppm, 1H exchangeable;11.5 ppm, 1H exchangeable.

Stage C

1-(7-Methoxy-1-naphthyl)-4-[2-(4-fluorobenzoyl)-aminoethyl]piperazinehydrochloride was obtained from the compound of the preceding stageaccording to the process described in Example 1, Stage E.

Yield: 40%.

Melting point: 221° C.

EXAMPLE 41-(7-Methoxy-1-naphthyl)-4-(2-bis(4-fluorobenzoyl)amino]ethyl)piperazinehydrochloride

To obtain this compound, the ether phase resulting duringcrystallization of the compound of Example 3 in base form isconcentrated and chromatographed on 20 g of 70-230 mesh silica using amixture of dichloromethane and acetone (95:5 V/V) as eluent.

Yield: 20%.

The base is then dissolved in isopropyl ether and converted to thehydrochloride with a solution of hydrochloric acid in diethyl ether.

Melting point: 234° C.

EXAMPLE 51-(7-Hydroxy-1-naphthyl)-4-[2-(4-fluorobenzoylamino)ethyl]piperazinehydrochloride

This compound was prepared according to the process described in Example2, from the compound of Example 3.

Yield: 80%.

Melting point: 230° C.

EXAMPLE 6 1-(7-Methoxy-1-naphthyl)-4-(2-tosylaminoethyl)-piperazinehydrochloride

This compound was prepared according to the method described in Example1, Stage E, from 1-(7-methoxy-1-naphthyl)-4-(2-aminoethyl)piperazine andtosyl chloride in solution in chloroform.

Yield: 44%.

Melting point: 277° C.

EXAMPLE 71-(7-Methoxy-1-naphthyl)-4-[2-(ethoxycarbonylamino)ethyl]piperazinehydrochloride

This compound was prepared as indicated in the preceding example, from1-(7-methoxy-1-naphthyl)-4-(2-aminoethyl)piperazine and ethylchloroformate in chloroform.

Yield: 55%.

Melting point: 208° C.

EXAMPLE 8 1-(7-Methoxy-1-naphthyl)-4-(2-nicotinoylaminoethyl)piperazinehydrochloride

This compound was prepared according to the process described in Example1, Stage E, from 1-(7-methoxy-1-naphthyl)-4-(2-aminoethyl)piperazine andnicotinoyl chloride.

Yield: 70%.

Melting point: 204° C.

EXAMPLE 91-(7-Methoxy-1-naphthyl)-4-[4-(4-fluorobenzoylamino)-1-butyl]piperazinehydrochloride Stage A

4-[4-(7-Methoxy-1-naphthyl)piperazino]butyronitrile

This compound was prepared according to the process described in Example1, Stage C, from 4-(7-methoxy-1-naphthyl)piperazine and4-bromobutyronitrile.

Yield: 98%.

Proton nuclear magnetic resonance spectrum (Solvent CDCl₃): 1.85 ppm, m,2H; 2.5 ppm, t, 2H; 2.6 ppm, t, 2H; 2.5-2.9 ppm, m, 4H; 3.1 ppm, m, 4H;3.9 ppm, s, 3H; 7.10 ppm, d, 1H; 7.15 ppm, d, 1H; 7.25 ppm, t, 1H; 7.5ppm, d, 1H; 7.55 ppm, s, 1H; 7.7 ppm, d, 1H.

Stage B 4-(7-Methoxy-1-naphthyl)-1-(4-amino-1-butyl)-piperazine

This compound was prepared from the compound described in the precedingstage according to the process described in Example 1, Stage D.

Yield: 80%.

Stage C

The expected compound was prepared from1-(7-methoxy-1-naphthyl)-4-(4-amino-1-butyl)piperazine and4-fluorobenzoyl chloride.

Yield: 60%.

Melting point: 224° C.

EXAMPLE 108-Carbamoyl-4-hydroxy-3-{2-[4-(7-methoxy-1-naphthyl)piperazino1ethyl}-2-methylimidazo1,5-a1pyrimidinehydrochloride Stage A

2-[4-(7-Methoxy-1-naphthyl)piperazino]ethanol hydrochloride

A mixture of 5 g of (7-methoxy-1-naphthyl)-piperazine, 3.4 g of2-iodoethanol and 5.5 g of potassium carbonate in 75 ml of acetonitrileis brought to reflux for 24 hours. The medium is then filtered and thesolvent is evaporated off. The residue is purified by chromatography on150 g of 70-230 mesh silica using a mixture of dichloromethane, methanoland ammonia solution (95:4.5:0.5 V/V) as eluent. The fractionscontaining the product are evaporated and the residue is dissolved in 20ml of ethanol, then 2.1 ml of 6N ethanolic hydrogen chloride are addeddropwise. The expected hydrochloride is obtained after precipitationwith ether.

Yield: 70%.

Proton nuclear magnetic resonance spectrum (Solvent DMSO-_(d6)): 3.1-3.8ppm, m+m, 2H+8H; 3.8-4.0 ppm, s+m, 3H+2H; 7.1-7.25 ppm, dd+d, 1H+1H; 7.3ppm, t, 1H;, 7.4 ppm, d, 1H; 7.6 ppm, d, 1H; 7.85 ppm, d, 1H; 10.7-11.1ppm, exchangeable complex.

Stage B

1-(7-Methoxy-1-naphthyl)-4-(2-chloroethyl)-piperazine

3.6 g of thionyl chloride are added dropwise to a suspension containing3.5 g of the compound obtained in the preceding stage in 100 ml ofchloroform. When the addition is complete, the medium is heated toreflux for 1 hour 30 minutes. The precipitate is then filtered off andwashed in the heated state in acetone.

Yield: 68%.

Melting point: 176° C.

Proton nuclear magnetic resonance spectrum (Solvent DMSO--_(d6)):3.1-3.8 ppm, m, 10H; 3.9 ppm, s, 3H; 4.15 ppm, t, 2H; 7.0-7.4 ppm,d+t+dd+d, 1H+1H+1H+1H; 7.6 ppm, d, 1H; 7.85 ppm, d, 2H; 11.3-11.7 ppm,exchangeable complex. Stage C

Ethyl 2-acetyl-4-[4-(7-methoxy-1-naphthyl)-piperazino]butyratehydrochloride

0.182 mol of ethyl acetoacetate is added at 0° C. to a suspensioncontaining 0.182 mol of sodium hydride in 800 ml of tetrahydrofuran. Thereaction medium is main-tained for one hour at 20° C. and 0.182 mol ofsodium iodide is then added. The mixture is cooled to 0° C. and 0.182mol of the compound obtained in the preceding stage is added. Themixture is brought t reflux for 12 hours and then concentrated undervacuum. The residue is taken up in water and extracted withdichloromethane. The oil obtained is purified by chromatography on acolumn of 70-230 mesh silica, eluting with a mixture of dichloromethaneand acetone (95:5 V/V).

Yield: 50%.

The ethyl 2-acetyl-4-[4-(7-methoxy-1-naphthyl)-piperazino]butyrateobtained is then diluted in ether, and the hydrochloride is precipitatedafter adding the requisite quantity of ethereal hydrogen chloride.

Proton nuclear magnetic resonance spectrum (Solvent CDCl₃): 1.3 ppm, t,3H; 2.25-2.6 ppm, m+s, 2H+3H; 3.0-4.1 ppm, s+m+m+m, 3H+4H+6H+1H; 4.2ppm, q, 2H; 7.1-7.35 ppm, 3H; 7.4 ppm, 1H; 7.6 ppm, dd, 1H; 7.8 ppm, d,1H; 12.3-13.3 ppm, 1H exchangeable.

Stage D

0.01 mol of 4-amino-5-carbamoylimidazole hydrochloride, 0.011 mol of theester prepared in the preced-ing step and 10.5 g of phosphoric acid aremixed. The mixture is brought to 80° C. for 30 minutes.

The mixture is hydrolyzed with ice and neutralized with concentratedsodium hydroxide to obtain the precipitation of8-carbamoyl-4-hydroxy-3-{2-[4-(7-methoxy-1-naphthyl)piperazino]ethyl}-2-methylimidazo[1,5-a]-pyrimidine.The product is then salified with methanolic hydrogen chloride.

Yield: 42%.

Melting point: 220° C.

EXAMPLE 118-Carbamoyl-4-hydroxy-2-methyl-3-(2-[4-(1-naphthyl)piperazino]ethyl}imidazo[1,5-a]pyrimidinehydrochloride Stage A

2-[4-(1-Naphthyl)piperazino]ethanol hydrochloride

This compound was prepared from 2-iodoethanol and (1-naphthyl)piperazineaccording to the process described in Example 10, Stage A.

Yield: 85%.

Stage B

1-(1-Naphthyl)-4-(2-chloroethyl)piperazine

This compound was prepared from the product obtained in the precedingstage and according to the process described in Example 10, Stage B.

Yield: 50%.

Proton nuclear magnetic resonance spectrum (Solvent CDCl₃): 2.6-3.0 ppm,t+m, 2H+4H; 3.1 ppm, m, 4H; 3.7 ppm, t, 2H; 7.1 ppm, dd, 1H, 7.6-7.3ppm, m, 4H; 8.2 ppm, m, 1H; 8.4 ppm, m, 1H.

Stage C

Ethyl 2-acetyl-4-[4-(1-naphthyl)piperazino]-butyrate hydrochloride

This compound was prepared according to the process described in Example10, Stage C, from ethyl acetoacetate and1-(1-naphthyl)-4-(2-chloroethyl)-piperazine.

Yield: 40%.

Proton nuclear magnetic resonance spectrum (Solvent CDCl₃): 1.3 ppm, t,3H; 2.0-2.3 ppm, m, 2H; 2.3 ppm, s, 3H; 2.45 ppm, t, 2H; 2.65 ppm, m,4H; 3.1 ppm, m, 4H; 3.6 ppm, t, 1H; 4.2 ppm, q, 2H; 7.05 ppm, dd, 1H;7.3-7.6 ppm, m, 4H; 7.8 ppm, m, 1H; 8.15 ppm, m, 1H.

Stage D

8-Carbamoyl-4-hydroxy-2-methyl-3-{2-[4-(1-naphthyl)piperazino]ethyl}imidazo[1,5-a]pyrimidinehydrochloride was prepared from the ester obtained in the precedingstage and 4-amino-5-carbamoylimidazole according to the processdescribed in Example 10, Stage D.

Yield: 30%.

Melting point: >260° C.

EXAMPLE 12 1-(7-Methoxy-1-naphthyl1-4-(2-phthalimidoethyl)-piperazinehydrochloride

A mixture of 1.5 g of (7-methoxy-1-naphthyl)-piperazine and 1.5 g of(2-bromoethyl)phthalimide in 100 ml of acetone is brought to reflux inthe presence of 1.6 g of potassium carbonate. The mixture is stirred for24 hours. The mixture is cooled, it is concentrated. The oil obtained isground in ether. The requisite quantity of ethereal hydrogen chloride isadded to obtain the expected hydrochloride.

Yield: 63%.

Melting point: 252° C.

EXAMPLE 131-(7-Methoxy-1-naphthyl)-4-[2-(2-thienoylamino)-ethyl]piperazinehydrochloride

This compound was prepared according to the process described in Example1, Stage E, from 1-(7-methoxy-1-naphthyl)-4-(2-aminoethyl)piperazine and2-thiophenecarbonyl chloride.

Yield: 81%.

Melting point: 237° C.

EXAMPLE 141-(7-Methoxy-1-naphthyl)-4-[2-(4-fluorobenzoylamino)ethyl]piperazinehydrochloride Stage A

1-(7-Methoxy-1-naphthyl)-4-benzyl-2,6-piperazinedione

126 mmol (2.2 equivalents) of carbonyldiimidazole are added to asuspension containing 58 mmol (1 equivalent) of N-benzyliminodiaceticacid in 200 ml of anhydrous tetrahydrofuran. The mixture is brought toreflux until the evolution of CO₂ has ceased. A solution containing 58mmol (1 equivalent) of 1-amino-7-methoxynaphthalene in 40 ml ofanhydrous tetrahydrofuran is then added to the above mixture. Theresulting mixture is brought to reflux for 20 hours, the solvent isevaporated off and the residue obtained is taken up with 300 ml ofanhydrous ethanol. The precipitate formed is filtered off and thendissolved in 200 ml of dichloromethane. The insoluble matter is filteredoff and the filtrate concentrated. The expected product is then obtainedafter taking up in isopropyl ether followed by filtration.

Yield: 82%.

Melting point: 178° C.

Stage B

1-(7-Methoxy-1-naphthyl)-2,6-piperazinedione

A suspension containing 43 mmol of the product obtained in the precedingstage, stirred in the presence of 1 g of palladium on charcoal (10% Pd)in 500 ml of methanol, is hydrogenated at atmospheric pressure and atroom temperature for 3 h 30 min. After filtration to remove the catalystand evaporation of the solvent, the expected product is obtained.

Yield: 97%.

Melting point: 232° C.

Stage C

1-(7-Methoxy 1-naphthyl)-4-(cyanomethyl)-2,6-piperazinedione

11 mmol of the product obtained in the preceding stage are stirred atroom temperature with 17 mmol of bromoacetonitrile and 13 mmol oftriethylamine in 60 ml of an anhydrous acetone/anhydrousdimethylformamide (50:50) mixture. After hydrolysis with 200 ml ofwater, the expected product is obtained after filtering off theprecipitate.

Yield: 64%.

Melting point: 204° C.

Stage D

1-(7-Methoxy-1-naphthyl)-4-(2-aminoethvl)-piperazine

13 ml of a 2M solution (4 equivalents) of borane/dimethyl sulfidecomplex are added slowly to a solution containing 6.5 mmol (1equivalent) of the product obtained in the preceding stage in 70 ml ofanhydrous tetrahydrofuran at 60 C. The mixture is brought to reflux for45 minutes while distilling off a dimethyl sulfide/tetrahydrofuranmixture. The reaction volume is kept constant during this distillationby adding tetrahydrofuran. After hydrolysis at room temperature with13.4 ml of 6N hydrochloric acid solution, the mixture is brought toreflux for 30 minutes.

The expected product is obtained after the addition of 54 ml of 2Nsodium hydroxide, by extraction with 3 times 100 ml dichloromethanefollowed by chromatography on silica gel using adichloromethane/methanol/ammonia solution (90:10:1) mixture as eluent.

Yield: 50%.

Stage E

1-(7-Methoxy-1-naphthyl)-4-2-(4-fluorobenzoylamino)ethyl]piperazinehydrochloride

The expected product is obtained as described in Stage C of Example 3.

EXAMPLE 15 1(7-Methoxy-1-naphthyl)-4-(2-butyrylaminoethyl)-piperazinehydrochloride

Using the procedure described in Example 14, but replacing4-fluorobenzoyl chloride in Stage E by butyryl chloride, the expectedproduct is obtained.

Yield: 91%.

Melting point: 190° C.

Elemental microanalysis:

    ______________________________________                                        Elemental microanalysis:                                                                C %  H %        N %    Cl %                                         ______________________________________                                        Calculated  64.35  7.72       10.72                                                                              9.05                                       Found       64.10  7.82       10.74                                                                              9.07                                       ______________________________________                                    

EXAMPLE 161-(7-Methoxy-1-naphthyl)-4-(2-cyclopropylcarbonylaminoethyl)piperazinehydrochloride

Using the procedure described in Example 14, but replacing4-fluorobenzoyl chloride in Stage E by cyclopropylcarbonyl chloride, theexpected product is obtained.

Melting point: 204° C.

Elemental microanalysis:

    ______________________________________                                        Elemental microanalysis:                                                                C %  H %        N %    Cl %                                         ______________________________________                                        Calculated  64.69  7.24       10.78                                                                              9.09                                       Found       64.48  7.58       10.68                                                                              8.86                                       ______________________________________                                    

EXAMPLE 171-(7-Methoxy-1-naphthyl)-4-[2-(4-fluorophenylsulfonamido)ethyl]piperazinehydrochloride

Using the procedure described in Example 14, but replacing4-fluorobenzoyl chloride in Stage E by 4-fluorobenzenesulfonyl chloride,the expected product is obtained.

Yield: 79%.

Melting point: 229° C.

Elemental microanalysis:

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %       Cl %  S %                                     ______________________________________                                        Calculated                                                                              57.55    5.67   8.75    7.39  6.68                                  Found     57.96    5.98   8.68    7.21  6.66                                  ______________________________________                                    

EXAMPLE 18 1-(7-Methoxy-1-naphthyl)-4-[2-(3-indolylcarboxamido)ethyl]piperazine hydrochloride

Using the procedure described in Example 14, but replacing4-fluorobenzoyl chloride in Stage E by 3-indolecarbonyl chloride, theexpected product is obtained.

Yield: 67%.

Melting point: 242° C.

Elemental microanalysis:

    ______________________________________                                        Elemental microanalysis:                                                                C %  H %        N %    Cl %                                         ______________________________________                                        Calculated  67.16  6.29       12.05                                                                              7.62                                       Found       67.04  6.45       11.96                                                                              7.72                                       ______________________________________                                    

EXAMPLE 191-(7-Methoxy-1-naphthyl)-4-2-(8-aza-7,9-dioxospiro[4.51dec-8-yl)ethyl]piperazinehydrochloride

Stages A and B are identical to those described in Example 10.

Stage C

A solution containing 0.49 g of 8-aza-7,9-dioxospiro[4.5]decane in 10 mlof dimethylformamide is added slowly to a suspension containing 0.13 gof 60% sodium hydride in 30 ml of dimethylformamide.

The mixture is brought to 70° C. for 30 minutes. After cooling, asolution containing 1 g of the product obtained in the preceding stageis added to the mixture and the resulting mixture is brought to refluxfor 12 hours.

The expected product is obtained after evaporation, purification bychromatography on silica using a dichloromethane/acetone (90:10) mixtureas elution solvent and precipitation of the hydrochloride in etherealhydrogen chloride.

Yield: 60%.

Melting point: 216° C.

Elemental microanalysis:

    ______________________________________                                        Elemental microanalysis:                                                                C %  H %        N %    Cl %                                         ______________________________________                                        Calculated  63.30  7.06       8.51 11.48                                      Found       63.66  7.06       8.27 11.74                                      ______________________________________                                    

                                      TABLE I                                     __________________________________________________________________________     ##STR35##                                                                    EX. No                                                                             NAPH    n R.sub.1         NMR spectrum (Solvent)                         __________________________________________________________________________          ##STR36##                                                                            2                                                                                ##STR37##                                                                                     ##STR38##                                     2                                                                                   ##STR39##                                                                            2                                                                                ##STR40##                                                                                     ##STR41##                                     3                                                                                   ##STR42##                                                                            2                                                                                ##STR43##                                                                                     ##STR44##                                     4                                                                                   ##STR45##                                                                            2                                                                                ##STR46##                                                                                     ##STR47##                                     5                                                                                   ##STR48##                                                                            2                                                                                ##STR49##                                                                                     ##STR50##                                     6                                                                                   ##STR51##                                                                            2                                                                                ##STR52##                                                                                     ##STR53##                                     7                                                                                   ##STR54##                                                                            2 NHCOOC.sub.2 H.sub.5                                                                           ##STR55##                                     8                                                                                   ##STR56##                                                                            2                                                                                ##STR57##                                                                                     ##STR58##                                     9                                                                                   ##STR59##                                                                            4                                                                                ##STR60##                                                                                     ##STR61##                                     10                                                                                  ##STR62##                                                                            2                                                                                ##STR63##      (DMSO-d.sub.6)  .sub.-s .sup.1 H NMR 2,6                                      ppm,  .sub.-s, 3H; 2.9-3.6 ppm,  .sub.-m,                                     10H; 3.75 ppm,  .sub.--m, 2H; 3.9 ppm,                                        .sub.-s, 3H; 7.1-7.25 ppm,  .sub.--m, 2H;                                     7.25 ppm, 1H exchangeable; 7.3 ppm                                            .sub.-t, 1H; 7.40 ppm,  -d, 1H; 7.45 ppm,                                     1H; exchange- - able; 7.6 ppm,  -d, 1H;                                       7.85 ppm,  -d, 1H; 8.15 ppm,  .sub.-s, 1H;                                    10.8 ppm, 1H exchangeable, 11.65 ppm, 1H,                                     exchangeable                                   11                                                                                  ##STR64##                                                                            2                                                                                ##STR65##      (DMSO-d.sub.6)  .sub.-s .sup.13 C NMR 17.3                                    ppm; 19.5 ppm; 49.4 ppm; 51.3 ppm; 53.9                                       ppm; 100.1 ppm; 115.0 ppm; 115.1 ppm;                                         123.1 ppm; 123.5 ppm; 123.9 ppm; 125.7                                        ppm; 125.8 ppm; 126.0 ppm; 127.8 ppm;                                         128.3 ppm; 132.5 ppm; 134.2 ppm; 147.6                                        ppm; 151.4 ppm; 155.8 ppm; 164.3 ppm           12                                                                                  ##STR66##                                                                            2                                                                                ##STR67##                                                                                     ##STR68##                                     13                                                                                  ##STR69##                                                                            2                                                                                ##STR70##                                                                                     ##STR71##                                     __________________________________________________________________________     .sub.-s = salt                                                                -b = base                                                                

PHAMACOLOGICAL STUDY EXAMPLE 20 Evaluation of the antihypertensiveactivity of the compounds of the invention

Mongrel dogs (male and female) are anesthetized with phenobarbital (30mg/kg i.v.) and then placed in artificial respiration (Bird Mark VIIrespirator). Arterial blood pressure is measured by means of a catheterplaced in the abdominal aorta via the femoral artery. This catheter isconnected to a pressure cell (Statham® R₂₃ D₆) linked to a recorder.

Heart rate is measured by means of a Gould Biotach®.

Sympathetic nervous activity is recorded from the renal nerve by meansof a silver electrode. The amplified signal is visualized on anoscilloscope (Tektronix 5115®) and then measured in μV by means of aGould integrator. The compounds under examination are administered i.v.The results of the study are given in Table II.

                  TABLE II                                                        ______________________________________                                                          EFFECT ON                                                                     ARTERIAL BLOOD EFFECT ON                                              DOSE    PRESSURE       HEART RATE                                   COMPOUNDS μg/kg                                                                              (mm/Hg)        (Beats/min.)                                 ______________________________________                                        Flesinoxan, (+) isomer                                                                   30  30 100                                                                            ##STR72##                                                                                    ##STR73##                                   Flesinoxan, reacemic                                                                     10  30 100 300                                                                        ##STR74##                                                                                    ##STR75##                                   EXAMPLE 3  3  10 30                                                                              ##STR76##                                                                                    ##STR77##                                   EXAMPLE 5  3 10 30                                                                               ##STR78##                                                                                    ##STR79##                                   EXAMPLE 13                                                                               1  3 10                                                                               ##STR80##                                                                                    ##STR81##                                   ______________________________________                                    

The results shown in Table II demonstrate that the compounds of theinvention are approximately 3-10 times as potent as the referenceproduct flesinoxan in racemic form or in the form of the (+) isomer.This isomer is the more active isomer of flesinoxan.

As regards sympathetic nervous activity, the results obtained with thecompound of Example 3 after i.v. administration of a dose of 10 μg/kgare given in FIG. 1.

EXAMPLE 21 Evaluation of the affinity for 5-HT_(1A) receptors

For the tests, hippocampal tissue obtained from decapitated Wistar ratswas used. The animals were sacrificed 48 hours before the experiment andthe isolated tissues were stored at -86° C. For the preparation of themembranes, the tissues were then homogenized using 20 volumes of 50 mMTris-HCl buffer solution (pH 7.7 adjusted using NH Cl at 25° C.) for onevolume of tissue, at a temperature in the region of 0° C, with aPolytron® homogenizer, and the whole was then centrifuged (35,000 g+20min at 4° C.). The pellet thereby obtained was suspended in 100 volumesof an incubation buffer solutions (60 M Tris, 10 μM pargyline, 4 M CaCl₂0.1% (w/v) ascorbic acid; pH adjusted to 7.7 with 5N HCl). The compoundsunder examination were also diluted in the incubation buffer, and thetest solutions were then prepared by adding 100 μof a solution of thecompound under examination and 100 μl of a solution of [³ H]--8--OH--DPAT, C=0.4 nM (specific radioactivity =205 Ci/mmol), into 12×75 mmglass tubes. Non-specific binding was determined by means of a 10 μMsolution of 5-hydroxytryptamine, and corresponds to 5-10% of the totalbinding.

The tubes were incubated for 30 min at 37° C., and the solutions werethen filtered through GF/B glass fiber filters treated with 0.1%polyethyleneimine (Whatman®). The filters were rinsed twice with 5 ml ofthe incubation buffer solution and were then placed in vials into which4.5 ml of "Picofluor scintillation fluid"®(Packard) were added. Theradioactivity was determined using external standards.

The pKi values were determined using the Cheung-Prusoff equation:

    -log (IC.sub.50 [1+[.sup.3 H]--8--OH--DPAT]/Kd).

The compounds of the invention have a great affinity for 5-HT_(1A)sites. The pKi values of the compounds of the invention are of the orderof 9.01 nmol/liter.

PHARMACEUTICAL PREPARATION EXAMPLE 22 Hard gelatin capsules containing a1-mg dose of1-(7-methoxy-1-naphthyl)-4-[2-(4-fluorobenzoylamino)-ethyl]piperazinehydrochoride [M.N.F.B.A.E.P.]

    ______________________________________                                        M.N.F.B.A.E.P.   1 mg                                                         Maize starch     15 mg                                                        Lactose          25 mg                                                        Talc             5 mg                                                         ______________________________________                                    

We claim:
 1. A compound selected from those of formula I: ##STR82## inwhich: n represents 1 to 4,R represents hydrogen atom, halogen atom,alkyl having 1 to 6 carbon atoms, hydroxyl or alkoxy having 1 to 6carbon atoms, R₁ represents a radical of formula A₁ : ##STR83## in whichR₂ represents a 2-thienyl radical, its stereoisomers and its additionsalts with a pharmaceutically, acceptable inorganic or organic acid. 2.Compound of claim 1 being1-(7-Methoxy-1-naphthyl)-4-[2-(2-thienoylamino)-ethyl]piperazine, or anaddition salts thereof with a pharmaceutically, acceptable inorganic ororganic acid.
 3. A pharmaceutical composition useful formodifying-5-HT_(1A) receptors containing as active principle aneffective 5-H-T_(1A) receptor-modifying amount of a compound as claimedin claim 1, in combination or mixed with a pharmaceutically, acceptable,inert excipient or vehicle.
 4. The pharmaceutical composition as claimedin claim 3, containing the active principle in amount of 0.05 to 10 mg.5. A method for treating an animal or human living body afflicted with acondition involving 5-HT_(1A) receptors selected from the groupconsisting of migraine, depression, anxiety, schizophrenia, stress, andpain, comprising the step of administering to the said living body anamount of a compound of claim 1 which is effective for alleviation ofsaid condition.
 6. A method for treating a living body afflicted withhypertension comprising the step of administering to the said livingbody an amount of a compound of claim 1 which is suitable foralleviation of said condition.